It is well known that many compounds have the capacity more or less for entering the subdermal layers of the skin eventually into the host's circulatory system. This process is said to be a passive penetration process. The major focus for the transdermal mode of treatment lies in the non-invasiveness thereof which obviates parenteral administration and its obvious disadvantages as well as the disadvantages attendant with the oral mode of administration such as gastrointestinal distress and the breakdown of the active ingredient due to metabolic and/or digestive processes. Generally the passive penetration activity of most active ingredients is not sufficient for most clinical purposes.
The durability of the delivery of physiologically active agents through the skin, i.e., transdermally, as opposed to other methods or parenteral administration or via the digestive system is based on many factors. The large surface area of the skin (about 1.8 sq. meters for the average adult man) and the large circulatory (about one-third of total body blood) and lymphatic networks available near the skin, the generally non-invasive nature of topical applications and their delivery through the skin, the convenience, the safety, the potential greater control of delivered agents, and the minimal side effects are just some of the advantages seen for this technique.
While not every and all agents may be suitable for transdermal delivery because of local irritation, allergic reactions, etc. most are indicated as suitable but, unfortunately, the greatest problem is overcoming the general barrier to drug penetration (or indeed to any material) of the skin. A drug must pass through the outer layer of skin or epidermis and into the dermis layer before being absorbed into the blood stream. The epidermis comprises two main parts, the stratum corneum and the stratum germinativum. The stratum corneum forms the outermost layer of the epidermis and consists of many stratified layers of compacted, flattened, keratinized cells which have lost their nuclei. This outermost layer serves as a physical barrier to percutaneous absorption. Because of the barrier effect of the skin, it has heretofore only been possible to deliver drugs that are "low-dose" drugs, in the range of 10 mg/day or less, or those of low molecular weight. In addition they have to have the proper lipophilic-hydrophilic balance to permit adequate absorption. It was recognized as early as the beginning of this century that lipid-soluble substances such as nonelectrolytes have a comparatively greater skin permeability than water-soluble substances, such as electrolytes.
The phenomenon of percutaneous absorption or transdermal permeation can be viewed as a composite of a series of steps in sequence, that is, adsorption of a penetrant molecule onto the surface layers of the stratum corneum, diffusion through it and through the viable epidermis, and finally through the capillary dermis and into the microcirculation. The great diffusional resistance of the stratum corneum has been demonstrated in a comparative absorption of drugs, like hydrocortisone. The mucous membranes in the rectal and vaginal regions permit the absorption of 26-29% of the steroid applied, while less than 2% of the applied dose is absorbed through the skin.
Compounds which are known or reported to enhance the transdermal delivery of drugs include dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate, alkyl lactams, and long-chain amides. Prior art patents of relevance to penetrating enhancers of physiologically active agents include U.S. Pat. Nos. 3,551,554 which describes dimethyl sulfoxide, U.S. Pat. No. 3,989,816 discloses 1-substituted azacycloheptane-2-one; U.S. Pat. No. 4,132,781 discloses a topical antibiotic plus 2-pyrrolidone or an n-lower alkyl-2-pyrrolidone, U.S. Pat. No. 4,017,641 also describes 2-pyrrolidone but with propylene glycol; others of interest are U.S. Pat. Nos. 3,903,256, 4,343,798, 4,046,886, 3,934,013; 4,070,462; 4,130,643, 4,130,667, 4,289,764; 4,070,462; 3,527,864, 3,535,422, 3,598,123, 3,952,099, 4,379,454, 4,286,592; 4,299,826; 4,314,557; 4,343,798; 4,335,115; 3,598,122; 4,405,616, 3,896,238, 3,472,931 and 4,557,934.
In U.S. Pat. No. 4,861,764 (Samour et al) certain 1,3-dioxolanes and 1,3-dioxanes are described as useful for enhancing the absorption of therapeutic agents through the skin.
It is also known that charged molecules may be transported across the skin utilizing iontophoresis. Iontophoresis is a process which induces an increased migration of ions or charged molecules in an electrolyte medium following the flow of electric current. The transport of the charged molecules is driven by the electric field established between the driving electrodes.
The technique was first conceived in 1908 when it was demonstrated that ions could be driven across the skin by means of an electric current. Numerous studies utilizing ophthalmological iontophoresis, cocaine and epinephrine iontophoresis for anesthesia were conducted. Because of tissue burning, electrical shocking of patients, and other technical problems from about 1921 to the early 1940's iontophoresis was virtually discarded while many uses were advanced, perhaps the widest use of iontophoresis up to recently is that of diagnosing cystic fibrosis by iontophoresing pilocarpine into the skin in order to obtain sufficient sweat for diagnosis.
The limitations of iontophoresis are governed by three significant factors--safety, convenience and predictability. Many systems in the past have used household current to power the devices and these placed the patient in considerable shock hazard should the device malfunction. Also, the possibility of burns was a marked deterrent. A second generation of devices functioned with a constant voltage so that varying current levels, depending upon the impedance of the body tissue being treated were generated; thus, although the possibility of direct electric shock was limited, the change of burning tissues remained, primarily because burns will result if the current density becomes too high. If a small area of tissue is burned, the resistance or impedance of this same tissue decreases and, with a constant voltage device, the current increases, thus compounding the problem. Also, constant voltage devices are not predictable as regards the amount of drug iontophoresed into any one region. Current varies inversely as the impedance of the tissue encountered and the actual quantity of the drug being iontophoresed is directly proportional to the current level, therefore, a frequent concern has been the repeatability of drug dosage in terms of quantity and rate of drug transfer with respect to time. Because of the limitations imposed by constant voltage controlled current devices evolved as the major delivery system in this field.
A fourth major factor which governs the use of iontophoresis is the ability to deliver adequate, clinically effective levels of active ingredient within the parameters of safety, convenience and predictability. Many drugs, particularly large molecules cannot be delivered in adequate levels without the need to use high current densities which can lead to the problems discussed above, in addition to the possibility of irreversible changes on the skin which may further limit drug dosage transmission and effectiveness.